The major objective of this proposed research program is to study the effect of structural changes on the metabolism and resulting biologic activity of antimetabolites, in particular antimetabolites of the purine-pyrimidine type that interfere with the synthesis or function of nucleotides or nucleic acids. The knowledge accumulated in this study will be used to design new antimetabolites with improved anticancer activity resulting from reduced catabolism, increased anabolism, a combination of these two, and activity against resistant cell lines. A great deal of information will be developed about the active sites of purine-pyrimidine metabolizing enzymes and about modes of binding to these sites, primarily from the effect of structural alterations on substrate specificites.